Moderate or low-risk alcohol consumption (defined by NIAAA as d4 drinks on any single day AND d14 drinks per week for men or d3 drinks on any single day AND d7 drinks per week for non-pregnant women) has been associated - despite its appellation - with a wide variety of health outcomes of the greatest import. Compared with abstainers or rare drinkers, moderate drinkers have been observed to have lower rates of coronary heart disease, congestive heart failure, ischemic stroke, diabetes, and cholelithiasis but higher rates of breast and possibly other cancers; relationships with fractures are less certain, although evidence suggests that moderate alcohol may simultaneously raise risk of trauma yet improve bone density. Perhaps most compellingly, moderate alcohol intake has been associated with a lower risk of all-cause mortality, chiefly reflecting its inverse associatio with cardiovascular mortality. Important limitations affect this body of evidence, however. Although large and consistent epidemiological studies have been conducted, strong concerns about residual confounding by both health status and health- seeking behavior exist. The existing experimental studies of alcohol are small and short and, while demonstrating plausible mechanisms by which moderate drinking would lower cardiometabolic risk, the lack of correspondence between similar studies of postmenopausal estrogen treatment and the randomized Women's Health Initiative clinical trial only heightens this concern. Given the widespread use of alcohol, the clear risks and costs of its overuse, the uncertain balance of risks and benefits of moderate use, and the complete lack of definitive clinical trial data, the urgent need for a clinical trial of moderate alcohol intake is unmistakable. In this Clinical Trial Planning Cooperative Agreement (U34) application, we propose to develop a multi-center, international, long-term, pragmatic randomized clinical trial of moderate drinking on the key clinical outcomes with which it has been associated - cardiovascular disease, cancer, diabetes, trauma, accidents, mortality, and progression to heavy or at-risk drinking. Building upon a team of established investigators and field centers with clinical trial and/or alcohol expertise (both i most cases) in North America, Asia, Europe, and Africa, we intend to develop a clinical trial protocol, recruit additional field centers, establish a data management network, and outline practical strategies for recruitment, intervention, monitoring, and outcome ascertainment across diverse settings. With a focus upon adults at higher cardiovascular risk to maximize efficiency, we will partner with NIAAA to develop a definitive clinical trial that can provide patients and clinicians worldwide with gold- standard advice about the effectiveness of moderate drinking in chronic disease prevention.